The association of menopause with cardiometabolic disease risk factors in low- and middle-income countries: a systematic review and meta-analysis

Importance Menopause is an integral part of women’s health and studies in high income countries have shown an increase in CMD risk factors in post- compared to premenopausal women. However, to date no study has combined and assessed such studies across LMICs. This would better inform early monitoring and intervention strategies for reducing CMD risk factor levels in midlife women in these regions. Objective To evaluate evidence from the literature on differences in CMD risk factors between pre- and post menopausal midlife women living in LMICs. Evidence Review A systematic review with meta-analysis of original articles of all study designs from the databases PubMed, PubMed Central, Scopus, and ISI Web of Science was conducted from conception until April 24, 2023. Studies that met the inclusion criteria were included in the analysis. Quality assessment of the articles was done using the Newcastle-Ottawa Scale, adapted for each study design. The study protocol was registered with the International Prospective Register of Systematic Reviews and adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. For the meta-analysis, fixed-effects models were used to pool the odds ratios (ORs), as measures of association. Findings Our search identified 4,849 relevant articles; 44 for the systematic review and 16 for the meta-analysis, in accordance with our inclusion criteria. Compared with premenopausal women, the postmenopausal stage was associated with metabolic syndrome (OR=1.18 (95 % CI 1.11–1.27)), high waist-to-hip ratio (OR=1.22 (95% CI 1.12–1.32)), hypertension (OR=1.10 (95% 1.04–1.16)), elevated triglycerides (OR=1.16 (95% CI 1.11–1.21)) and elevated plasma glucose (OR=1.21 (95% CI 1.15–1.28)). Conclusions and Relevance This study confirmed that CMD risk factors are present at higher levels in post- than premenopausal women. This demonstrates an urgent need for public health policies that focus on early monitoring and interventions targeted at reducing CMD risk and related adverse outcomes in midlife women in these nations.


Introduction
Studies have shown that hormonal changes along the hypothalamus-pituitary-ovarian axis during the menopause transition (MT) may be associated with adverse changes in cardiometabolic health in midlife women. 1,2One report from the Study of Women Across the Nation (SWAN), highlighted that despite the levels of total testosterone (T) remaining constant during the MT, the more rapid decline of estradiol (E2) creates a more androgenic sex hormone profile termed the relative androgen excess, which contributes to increased risk of the metabolic syndrome. 3Reports have also shown that declining E2 and increasing follicle stimulating hormone (FSH) levels during the MT are associated with drastic changes in body fat composition and distribution. 4,5These changes have been associated with central obesity and increased secretion of pro-inflammatory adipokines and free fatty acids which in turn increase the risk of insulin resistance, and hypertension. 6,7udies have shown a higher prevalence of obesity among women compared with men from LMICs, and these differences are reported to be more apparent in midlife than in childhood years. 8As a result, an in-depth analysis of the contribution of menopause to obesity and associated CMD risk factors in women in LMICs is warranted.Furthermore, a meta-analysis showed that women from LMICs reach menopause at an earlier age than those from high-income countries (HICs). 9In this meta-analysis involving thirty-six studies across the six continents, the mean (with 95% CIs) age at menopause was lower in Africa (48.4 (48.1-48.7)),Latin America (47.2 (45.9-48.6)),Asia (48.8 (48.1-49.4)),and the Middle East (47.4(46.9-47.8)),compared to Australia (51.3 (49.8-52.8)),Europe (50.5 (50.0-51.1))and the United States (49.1 (48.8-49.4)). 9Early age at menopause has been linked with increased CMD risk factors, 10 therefore suggesting heightened risk in LMICs.
At present, there are no data quantifying the differences between the levels of CMD risk factors in pre-and postmenopausal women in studies from LMICs despite an increasing prevalence of obesity and associated CMD in these countries.The objective of this systematic review and meta-analysis was therefore to evaluate evidence from the literature on the links between menopause and CMD risk factors in midlife women living in LMICs.

Protocol
This systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Review (PRISMA) 2020 guidelines and was registered with the International Prospective Register of Systematic Reviews (PROSPERO) with the number CRD42021295401. 11

Search strategy and data sources
We searched the databases; PubMed, PubMed Central, Scopus, and ISI Web of Science, for original articles of all study designs from inception until April 24, 2023.The query terms consisted of the key words related to "premenopause", "postmenopause", "cardiometabolic disease risk factors" and "LMICs".The search strategy is fully detailed in the Supplemental Table 1.

Eligibility criteria
We only included studies conducted in LMICs as defined by the World Bank list of economies (June 2020). 12These studies assessed differences in CMD risk factors between pre-and postmenopausal women.The inclusion criteria were: 1) studies that enrolled both pre-and postmenopausal women, 2) studies evaluating differences in CMD risk factors according to the menopausal stage, and 3) studies published in English.Articles were excluded if they were reviews, editorials, or preliminary reports.

Data extraction
One researcher (RPC) independently screened all initially identified articles and abstracts using the Rayyan software. 13The number of included and excluded records is mapped in Figure 1.Studies deemed to potentially meet inclusion criteria underwent a full-text assessment by two independent reviewers (RPC and NGM).The consensus between two authors satisfied the inclusion criteria.Disagreements were resolved by a third reviewer, NJC.

2.2.4
Quality Assessment-Two reviewers, RPC and NGM, independently used the modified Newcastle-Ottawa Scale (NOS) 14 to assess the methodological quality of selected articles.Two separate NOS tools developed for cross-sectional and longitudinal studies were used in the quality assessment.Based on the total score, the risk of bias was assigned into two categories: low risk (7-9) and high risk (0-6).Only studies with a low risk of bias were included in this study.Any disagreements were referred to a third reviewer, NJC.

Statistical Analyses
To quantitatively assess the association between menopause stage and CMD risk factors i.e. metabolic syndrome (MetS), blood pressure, triglycerides, HDL-C, blood glucose, and carotid intima thickness (cIMT) levels, obesity, waist circumference (WC), waist-to-hip ratio (WHR) and type 2 diabetes mellitus, we calculated the pooled estimates of odds ratios and associated 95% confidence intervals using the inverse variance fixed-effect model.In the analyses, studies were grouped based on the defined outcome of interest (CMD risk factor).
Heterogeneity between studies was assessed using Cochran's Q statistic (p<0.01 indicative of heterogeneity) and the I 2 index (values 25%, 50% and 75% suggestive of low, moderate, and high heterogeneity, respectively).All statistical analyses were performed using Stata 16.1 (StataCorp LLC, College Station, TX).

Search results
Figure 1 shows the PRISMA flow chart on the screening and selection of the research articles.Briefly, the initial search identified 7,124 abstracts.After removing duplicates, 4,849 titles and abstracts were screened.Of these, 4,767 irrelevant articles were excluded, leaving 82 articles for full-text review.Thirty-eight of the 82 articles were excluded in the quality assessment.As a result, 44 articles constituted the systematic review.Of these 44 articles, 16 were eligible for the quantitative analysis and 28 were excluded due to the following reasons: reporting of a CMD risk factor that was uncommon to other articles (n=3), no combined comparison of pre-and postmenopausal stages on CMD risk factors (n=1), different definition criterion for MetS (n=1), and studies that did not report odds ratios as measures of association (n=23).

Primary outcomes
Figure 2 shows the combined effect size estimates in studies that evaluated differences in CMD risk factors according to menopausal stage.Overall, postmenopausal stage was associated with greater CMD risk as supported by significant odds ratios for MetS, hypertension and high triglyceride, fasting blood glucose, waist circumference, and WHR levels.However, odds ratios were not significant for BMI, HDL-C and cIMT levels in postrelative to premenopausal stage (Figure 2).The individual forest plots for each CMD risk factor are shown in the Supplemental Figures 1-11.

Discussion
This systematic review and meta-analysis on midlife women from LMICs show that the postmenopausal stage is associated with higher risk of MetS, elevated triglycerides, elevated blood glucose, high blood pressure, and high waist circumference but no differences when obesity, HDL-C and cIMT levels were compared between the two menopausal groups.These observations highlight a disproportionate burden of CMD risk factors in postcompared to premenopausal women in LMICs.
Our study broadens the understanding of the association of menopause with CMD risk factors by combining studies from LMICs into a large sample size (40 517 participants).Our findings are similar to a meta-analysis on MetS which included studies from around the world 59 .In their analysis, postmenopausal women were 3.5 times more likely to develop MetS compared to premenopausal women. 59Furthermore, the higher prevalence of the individual components of MetS in post-than in premenopausal women observed in that study, corroborate our findings.
In longitudinal studies from HICs, menopause has been shown to have differential effects on CMD risk factors.In the SWAN study, MetS, total cholesterol, LDL-C, HDL-C, and apo-B lipoproteins were independently associated with menopause only in the first year after FMP. 1,2The study also showed no influence of menopause on BMI, blood glucose, insulin, triglyceride, and blood pressure levels. 2 In the Atherosclerosis Risk in Communities (ARIC) study, the progression of MetS was rapid during the MT but it decreased after the FMP, which was more prominent in African Americans than White women. 60In the Melbourne Women's Midlife Health Project (MWMHP) study, HDL-C levels increased around the first year before FMP but decreased in the first year postmenopause. 61Other changes in blood lipids (triglycerides and LDL-C), BMI and diastolic blood pressure were only related to chronological ageing or one of the traditional risk factors. 61Furthermore, the Radiation Effects Research Foundation (RERF) study showed that total serum cholesterol levels increased from three years before FMP to one-year post-FMP whereas increased BMI and systolic blood pressure were associated with chronological ageing but not menopause. 62uthrie et al., observed that women gained an average of approximately 2.1 kilograms over five years, but these differences were not menopause related.However, the study showed that waist circumference and waist-hip ratio increased with MT. 63 There are many possible reasons for these different outcomes across studies, as also observed in the current systematic review, including differences in sample size, ethnicity, and time points at which CMD risk factors were measured.However, it is interesting to note that in these studies changes in BMI were not related to the menopause but changes in waist and WHR were, and this was also observed in the current meta-analysis.
The differences in CMD risk factor levels between pre-and postmenopausal women may relate to hormonal changes during the MT.In the SWAN study, menopause was associated with increasing bioavailable T, and declining E2 and sex hormone binding globulin (SHBG) levels. 1 The changes in testosterone and SHBG were associated with the MetS and its components.However, neither baseline E2 levels nor its decline during menopausal transition was associated with MetS. 1,60In the age-adjusted analyses, the T:E2 ratio and free androgen index (FAI) increased by approximately 10% from baseline over the five years of follow-up.Supporting evidence from one meta-analysis study showed that women with type 2 diabetes mellitus had higher T but lower SHBG levels than controls 64 .It is hypothesised that the association between SHBG and MetS is mediated by the inhibitory effect of insulin on the synthesis of SHBG. 65The association of sex hormone levels with CMD risk factors during menopause indicates that hormone therapy may be a useful intervention strategy for these diseases.However, the feasibility of using hormone therapy is debatable in under-resourced healthcare systems and very few studies have investigated its use in such environments.In a large cross-sectional study across 11 Latin American countries, the Collaborative Group for Research of the Climacteric in Latin America (REDLINC) showed that the current use of menopausal hormonal therapy (MHT) was associated with reduced risk of MetS. 66Furthermore, a study from Brazil showed that the use of MHT was associated with a lower risk for hypertension. 67However, these were cross-sectional studies and the use of MHT in these studies was low (12.5%). 66

Limitations and strengths
The present study has some limitations.Firstly, the number of identified articles per CMD risk factor in our analyses were small; thus, we could not investigate sources of heterogeneity further.Secondly, the studies assessed in the meta-analysis were dominated by large studies from China with none available from sub-Saharan Africa.Thirdly, our analyses were based on observational data and were therefore limited by study design as far as potential unmeasured confounders and direction of associations were concerned.Despite this, our study provides a comprehensive review of the current literature on this topic in LMICs and was guided by a registered protocol.

Conclusions
The results of this systematic review and meta-analysis show that menopause is associated with an increased risk for CMD risk factor levels in LMICs.Therefore, it is important to focus on prevention strategies such as lifestyle and behavioural changes to mitigate the development of CMD in midlife women in these countries.However, it must be noted that this analysis included a small number of studies with high levels of heterogeneity.More studies are therefore required in LMICs to investigate the relationship of menopause with CMD risk factors and to develop cost-effective interventions for these diseases.

Figure 1 .
Figure 1.PRISMA flow chart of literature screening and selection.PRISMA -preferred reporting items for systematic reviews and meta-analysis

Table 1 CMD risk factors and corresponding articles examined CMD risk factor Number of articles examined
BP-blood pressure, cIMT-carotid intima media thickness, CMD-cardiometabolic disease, DM-diabetes mellitus, MetS-metabolic syndrome, Others-Fat mass, visceral and subcutaneous adipose tissues, WC-waist circumference, and WHR-waist hip ratio.